Conventional approaches to treating cancer, including hematologic malignancies, and to predicting and assessing cancer and cancer cell responses to specific treatment regimens rely on properly classifying the type of tumor present. Proper classification, in turn, relies primarily on clinical features, tumor cell morphology, tumor cell immunophenotype and, to a lesser extent, on tumor cell chromosomal abnormalities. However, even within a given tumor type, response to specific treatment regimens is, often, quite variable, and analyses at the molecular level reveal that the tumor types defined by conventional classification schemes are, often, quite heterogeneous.
Recent efforts to classify tumors, including hematologic malignancies, have, therefore, focused on identifying the specific genetic abnormalities or molecular triggers that drive the growth or pathology of specific tumor types. Such genetic abnormalities or molecular triggers can then serve as markers of disease and/or as targets for therapy. Increasing evidence implicates aberrant expression of microRNAs (miRNAs) in most, if not all, human malignancies, and suggests that they may indeed act as either/both tumor suppressors or as oncogenes, and can have effects in numerous cancers which may have a common pathway, or in specific cancers which have particular miRNA initiators or modulators (Visone R and Croce C M (2009) Am J Pathology 174(4):1131-1138; Garzon R et al (2009) Ann Rev Med 60:167-179; Lui W-O et al (2007) Cancer Res 67(13):6031-6043).
MicroRNAs (miRNAs) are ubiquitous regulators of biological processes involved in normal development, in differentiation and in diseases, including cancer. They act by regulating gene expression at the transcriptional and translational levels (Bartel et al (2004) Cell 116:281-297). miRNAs were initially discovered by analysis of mutations causing developmental defects in Caenorhabditis elegans (Lee R. C. et al (1993) Cell, 75, 843-854) and altered miRNA expression has been further demonstrated in human cancer, including leukemia (Calin G. A. et al (2004) PNAS USA 101: 11755-11760; Hayashita Y et al (2005) Cancer Res 65:9628-9632; Johnson S. M. et al (2005) Cell 120:635-647; Lu J et al (2005) Nature 435:834-838; Venturini L et al (2007) Blood 109:4399-4405). MicroRNAs (miRNA) regulate gene expression in a sequence specific manner by hybridization and recruitment of multi-protein complexes to complementary messenger RNA (mRNA) target sequences. miRNA function can transiently be antagonized by antagomirs—chemically modified oligonucleotides complementary to individual miRNAs.
A single miRNA can target hundreds of messenger RNAs and thereby modulate protein output from their respective genes (Bartel D P (2009) Cell 136:215-233). Therefore a single or specific set of miRNAs may control discrete physiological processes by regulating the production of a few critical proteins that coordinate single or interrelated cellular events (e.g., cell proliferation) (Baltimore D et al (2008) Nat Immunol 9:839-845; Bartel D P (2009) Cell 136:215-233).
The 17˜92 cluster of miRNAs is highly expressed in hematopoietic cancers and enhances lymphoproliferation and c-Myc-induced leukemogenesis/lymphomagenesis in vivo (He, et al., 2005) (Xiao, et al., 2008). The 17˜92 cluster and its paralogues are also expressed in diverse solid tumors, including those derived from breast, colon, lung, pancreas, prostate, and stomach (Volinia, et al., 2006) (Petrocca, et al., 2008). Thus far, however, the function of and the targets regulated by individual miRNAs, in particular of those encoded on polycistronic transcripts, such as the 17˜92 cluster, are largely unknown.
Although numerous miRNAs are known and have been identified (known miRNAs are accessible by name with sequence information and characteristics via public database(s) including the miRBase database, mirbase.org; Griffiths-Jones S (2003) Methods Mol Biol 342:129-138), their specific roles in initiation and/or progression of disease(s) and their particular value as targets for therapies or as modulators of disease, including cancer remain largely ill-defined. Therefore, it should be apparent that there still exists a need in the art for a specific elucidation of the relevance of individual or collective miRNAs in cancers, including in specific cancers, for diagnosis and management of disease and for the development of specific therapies directed against individual or collective miRNAs for cancer.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.